Deep whole-genome analysis of 494 hepatocellular carcinomas

Lei Chen (), Chong Zhang, Ruidong Xue, Mo Liu, Jian Bai, Jinxia Bao, Yin Wang, Nanhai Jiang, Zhixuan Li, Wenwen Wang, Ruiru Wang, Bo Zheng, Airong Yang, Ji Hu, Ke Liu, Siyun Shen, Yangqianwen Zhang, Mixue Bai, Yan Wang, Yanjing Zhu, Shuai Yang, Qiang Gao, Jin Gu, Dong Gao, Xin Wei Wang, Hidewaki Nakagawa, Ning Zhang, Lin Wu (), Steven G. Rozen (), Fan Bai () and Hongyang Wang ()
Additional contact information
Lei Chen: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital
Chong Zhang: Peking University
Ruidong Xue: Peking University Health Science Center
Mo Liu: Duke-NUS Medical School
Jian Bai: Berry Oncology Corporation
Jinxia Bao: Nanjing University
Yin Wang: Berry Oncology Corporation
Nanhai Jiang: Duke-NUS Medical School
Zhixuan Li: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital
Wenwen Wang: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital
Ruiru Wang: Berry Oncology Corporation
Bo Zheng: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital
Airong Yang: Berry Oncology Corporation
Ji Hu: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital
Ke Liu: Berry Oncology Corporation
Siyun Shen: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital
Yangqianwen Zhang: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital
Mixue Bai: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital
Yan Wang: Berry Oncology Corporation
Yanjing Zhu: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital
Shuai Yang: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital
Qiang Gao: Fudan University
Jin Gu: Tsinghua University
Dong Gao: CAS
Xin Wei Wang: National Cancer Institute
Hidewaki Nakagawa: RIKEN Center for Integrative Medical Sciences
Ning Zhang: Peking University Health Science Center
Lin Wu: Berry Oncology Corporation
Steven G. Rozen: Duke-NUS Medical School
Fan Bai: Peking University
Hongyang Wang: National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital

Nature, 2024, vol. 627, issue 8004, 586-593

Abstract: Abstract Over half of hepatocellular carcinoma (HCC) cases diagnosed worldwide are in China1–3. However, whole-genome analysis of hepatitis B virus (HBV)-associated HCC in Chinese individuals is limited4–8, with current analyses of HCC mainly from non-HBV-enriched populations9,10. Here we initiated the Chinese Liver Cancer Atlas (CLCA) project and performed deep whole-genome sequencing (average depth, 120×) of 494 HCC tumours. We identified 6 coding and 28 non-coding previously undescribed driver candidates. Five previously undescribed mutational signatures were found, including aristolochic-acid-associated indel and doublet base signatures, and a single-base-substitution signature that we termed SBS_H8. Pentanucleotide context analysis and experimental validation confirmed that SBS_H8 was distinct to the aristolochic-acid-associated SBS22. Notably, HBV integrations could take the form of extrachromosomal circular DNA, resulting in elevated copy numbers and gene expression. Our high-depth data also enabled us to characterize subclonal clustered alterations, including chromothripsis, chromoplexy and kataegis, suggesting that these catastrophic events could also occur in late stages of hepatocarcinogenesis. Pathway analysis of all classes of alterations further linked non-coding mutations to dysregulation of liver metabolism. Finally, we performed in vitro and in vivo assays to show that fibrinogen alpha chain (FGA), determined as both a candidate coding and non-coding driver, regulates HCC progression and metastasis. Our CLCA study depicts a detailed genomic landscape and evolutionary history of HCC in Chinese individuals, providing important clinical implications.

Date: 2024
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DOI: 10.1038/s41586-024-07054-3

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